Reninangiotensin System

Many factors regulate RBF and GFR, but perhaps the most important is the renin-angiotensin system (RAS). Not only does the RAS regulate renal hemodynamics, but it is also more globally involved in regulating the ionic composition and volume of the extracellular fluid, and the systemic blood pressure. Blood pressure within the kidney is tightly regulated and is sensed by mechanisms that feed back and regulate systemic blood pressure through the RAS. Modified vascular smooth muscle cells, referred to as granular cells or juxtaglomerular cells, are present within the afferent arteriole. These cells store the enzyme renin in numerous cytoplasmic secretory granules, and they are extensively coupled to mesangial and smooth muscle cells by gap junctions. Juxtaglomerular cells release renin in response to an increase in intracellular cAMP or a fall in cytoplasmic Ca2+. The effect of cAMP is understandable because it is the intracellular second messenger for receptors that respond to sympathetic afferent nerves and circulating catecholamines. on the other hand, the response to intracellular Ca2+ is opposite from most systems in which an increase in Ca2+ stimulates secretion. However, decreased stretch in the afferent arteriole and juxtaglomerular cells, as would occur when the blood pressure falls, closes Ca2+ channels and lowers intracellular Ca2+ in these cells. As discussed later, the resulting release of renin counteracts the fall in blood pressure, thus completing a negative feedback system.

Renin itself has no direct hemodynamic effects, however, as shown in Fig. 9, it acts as a protease that cleaves the decapeptide angiotensin I from a specific a2-globulin (angiotensinogen) circulating in the blood. A second protease, angiotensin-converting enzyme (ACE), in turn cleaves two amino acids from angioten-sin I to produce the active octapeptide angiotensin II. ACE is found primarily in the lungs, but it is also present in the kidneys and other tissues where it rapidly converts angiotensin I to angiotensin II.

As illustrated in Fig. 9, angiotensin II has two major systemic effects: (1) It is a direct vasoconstrictor that acts on resistance vessels throughout the body, resulting in an elevation of total peripheral resistance and blood pressure; and (2) it acts via receptors in the adrenal cortex to increase secretion of the hormone aldosterone. As discussed later in relation to the function of the distal nephron (see Chapter 27), aldosterone increases the

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